TNFalpha blockade with anti-TNFalpha or soluble TNF receptor activates disease in patients with multiple sclerosis; in murine experimental allergic encephalomyelitis (EAE); in (NZBxNZW) F1 "lupus" nephritis; and variably in type 1 diabetes (T1DM) in non-obese diabetic (NOD) mice (1-10). In rheumatoid arthritis, TNF blockade is therapeutic, but approximately 15% of patients develop anti-dsDNA antibodies, 0.2% develop SLE, and a small number develop CNS and laboratory findings suggestive of multiple sclerosis. In adult NOD mice, systemic administration of non-toxic doses of TNFalpha delays the onset and decreases the incidence of T1DM. Several reports (19, 20, 48) present evidence that chronic TNFa exposure decreases T cell receptor signaling. On the other hand TNFalpha blockade appears to increase T cell effector function. These effects of TNF and anti-TNF on the TNF and TCR signaling pathways will be analyzed in several T cell systems by gene expression profiling on cDNA microarrays, and by specific immunoblotting with anti-phosphotyrosine and anti-phosphoserine. Paradoxically, TNFalpha treatment in the neonatal period leads to an earlier onset and increased incidence of T1DM in NOD mice. Further, neonatal anti-TNF treatment completely prevents T1DM in NOD mice. In neonatal NOD mice, TNFalpha decreases the already low CD4+, CD25+ regulatory T cell population, while anti-TNF dramatically increases the number of these regulatory T cells; effects which could explain the unexpected results of these treatments. Several findings (23, 27) suggest that these effects may be due to the known ability of the TNFa p75 receptor (TNFR2) to mediate apoptosis in mature, activated, peripheral T cells (27). This possibility will be tested in NOD.TNFR2- /- and NOD.TNFR1-/- mice. The results of these studies will aid in finding ways to prevent the side effects of therapeutic TNF blockade in patients, and will also aid in understanding the functions of TNFR2.